The goal of the proposed work is the development of statistical mechanical models designed to disect the nature and relative importance of short, medium and long range interactions and topological constraints on the folding transition of predominantly alpha-helical proteins. Initially the proposed work focuses on the further development of the equilibrium and kinetic theory of the helix-coil transition in alpha-helical, two-chain, coiled coils such as the important muscle regulatory protein tropomyosin. These architecturally simple systems are not only of great intrinsic Biochemical interest (e.g. tropomyosin plays an important role in muscle contraction) but also possess many qualitative aspects of the globular protein folding process; insights gained from these studies will be employed to examine the folding transition in globular proteins. Specifically, the proposed work on coiled coils and globular protein models comprises the following (1) the further development and application of the equilibrium theory of the helix-coil transition in coiled coils to provide a semi- quantitative theory of all extant experimental data on noncrosslinked, singly and doubly crosslinked rabbit alpha-and beta-tropomyosin. (2) The investigation of the effect of crosslink induced stress on the coiled coil structure through the construction of tropomyosin fragments using the ECEPP/2 procedure of Scheraga et al., followed by potential energy minimization. (3) Employing dynamic Monte Carlo simulations and analytic models, the kinetic theory of the coiled coil helix-to- random coil transition will be extended to include loop entropy (the reduction in configurational entropy when the ends of a random coil are constrained relative to when they are free, an effect of crucial importance at equilibrium) and for noncrosslinked molecules, chain dissociation an interchange between the out-of-register states of the two chains. Attempts will be made to identify experimental signatures indicative of the presence of the various relaxation mechanisms. (4) An equilibrium and kinetic theory of the native to denatured transition in model globular proteins composed of multiply interacting helices joined together by loops or bends will be developed. These studies are designed to test the conjectures that loop entropy is largely responsible for the validity of the equilibrium two state model of single domain globular protein folding and for the kinetic stabilization of the native state. (5) To elucidate plausible nascent folding pathways, Brownian dynamics simulations of schematic models are proposed.